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JNCI:科学家发现新淋巴结转移灶不会形成新生血管

来源:生物谷 2015-06-29 13:21

                                                             

2015年6月29日讯 /生物谷BIOON/ --有研究表明使用抗血管生成药物阻断新血管生长对于提高一些癌症的治疗效果具有一定作用,但临床数据表明这些药物在抑制新转移灶形成方面发挥的作用并不尽如人意。近日,来自美国马萨诸塞总医院癌症中心的研究人员发现了导致这一结果发生的一个可能原因,相关研究结果发表在国际学术期刊Journal of the National Cancer Institute上。
 
在这项研究中,研究人员发现癌细胞在淋巴结形成的新转移灶的生长并不需要新生血管的作用,这些新转移灶可以利用已有的血管进行营养供给。淋巴结是癌症传播的一个常见转移灶形成部位。
 
对于多数类型的实体瘤来说,淋巴结转移灶的形成标志着肿瘤恶性程度更高,需要进行化疗以及其他系统性疗法,在全身范围内进行癌症治疗。但淋巴结转移灶在癌症传播中所发挥的真正作用一直存在争议,一些专家认为淋巴结转移灶代表着原发肿瘤本身的一种传播能力,而另外一些学者认为淋巴结转移灶的形成是肿瘤向全身其他部位转移过程中最为关键的步骤,具有转移性的癌细胞通过淋巴结进入血液循环系统,播撒癌症之种。
 
在之前一项研究中,研究人员发现抗血管生成疗法并不能阻止淋巴结转移灶的发生和生长,而在这项研究中,研究人员利用一种新的肿瘤小鼠模型首次发现淋巴结的发生和生长过程中不存在新血管的发育过程,同时,一些血管生成诱导因子以及淋巴结转移灶中一些与血管生成有关的基因表达水平都没有发生增加。研究人员还对结肠癌和头颈癌病人的淋巴结转移灶进行了分析,也没有发现血管新生的证据。
 
研究人员还利用两种作用机制不同的血管生成抑制剂对小鼠模型进行处理,没有发现血管密度以及淋巴灶生长存在任何变化。最后,研究人员将进行了抗血管生成治疗的结肠癌病人淋巴结转移灶与没有进行该治疗的结肠癌病人淋巴结转移灶进行了对比,结果表明两者淋巴结转移灶中血管密度没有差别。
 
总得来说,这项研究表明抗血管生成药物在抑制新淋巴结转移灶形成方面没有作用是因为淋巴结转移灶形成过程中没有发生血管的新生过程,这为癌症的临床治疗以及药物选择使用提供了重要信息。(生物谷Bioon.com)
 
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Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases
 
Han-Sin Jeong*, Dennis Jones*, Shan Liao, Daniel A. Wattson, Cheryl H. Cui, Dan G. Duda, Christopher G. Willett, Rakesh K. Jain and Timothy P. Padera
 
Background: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported.
 
Methods: Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9-12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided.
 
Results: Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm2, 95% CI = 149 to 365 vessels/mm2; bevacizumab group mean = 327 vessels/mm2, 95% CI = 140 to 514 vessels/mm2, P = .78).
 
Conclusion: We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases.
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